Parasites are organisms that live on or within another organism (the host) and harm the host. Diseases caused by parasites such as protozoa and helminths are among the leading causes of death and disease in tropical and subtropical regions of the world.
Malaria is an infectious disease that causes severe morbidity and mortality with an estimated 300-500 million cases worldwide and more than 1 million deaths annually in sub-Saharan Africa alone. The disease is caused by protozoan parasites of the genus Plasmodium, transmitted by mosquitoes. The most serious forms of malaria are caused by Plasmodium falciparum and Plasmodium vivax, but other species (e.g., Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi) can also infect humans.
Among the murine malarial parasites, Plasmodium chabaudi (P. chabaudi) AS provides a unique experimental model to study the erythroid stage of the disease (Li, C. et al., 2001. Med. Microbiol. Immunol. (Berl) 189:115-126). P. chabaudi AS produces an infection in mice that shares many similarities with P. falciparum malaria in humans, including anemia, splenomegaly, hepatomegaly, renal alterations, hypoglycemia, and parasite sequestration (Cox, J. et al., 1987. Parasite Immunol. 9:543-561; Landau, I. and Gautret, P. 1998. Animal models: rodents. In Malaria, Parasite Biology, Pathogenesis, and Protection. I. W. Sherman, editor ASM Press, Washington D.C., pages 401-417). Among the murine malarial parasites, Plasmodium berghei (P. berghei) ANKA provides a unique model to study the cerebral stage of the disease (Hunt, N. H. et al., 2006 Int. J. Parasitol 36: 569-582). P. berghei ANKA produces an infection in mice that shares many similarities with cerebral malaria in humans, including sequestration of infected erythrocytes at the blood brain barrier, and appearance of cerebral symptoms such as fever, tremors, paralysis, coma and death.
In humans, malaria provides a clear example of host genetic factors influencing onset, progression, type of disease developed and ultimate outcome of infection (Hill, A. V. 1998. Annu. Rev. Immunol. 16: 593-617). Epidemiological data, together with linkage and association studies have shown that selection pressure from the parasite has caused retention of disease-associated but malaria-protective alleles in the human population, suggesting co-evolution of the host and parasite. Such otherwise deleterious alleles include those causing sickle cell anemia (Allison, A. C. 1954. Br. Med. J. 1(4857): 290-294; Willcox, M. A. et al., 1983. Ann. Trop. Med. Parasitol. 77: 239-246), thalassemias (Weatherall, D. J. 2001. Nat. Rev. Genet. 2: 245-255), and glucose-6-phosphate dehydrogenase deficiency (Ruwende, C. et al., 1995. Nature 376: 246-249). Polymorphisms in other erythroid proteins, including common variants of the Duffy antigen (Miller, L. H. et al., 1976. N. Engl. J. Med. 295: 302-304), the erythrocyte band 3 (anion exchanger) (Allen, S. J. et al., 1999. Am. J. Trop. Med. Hyg. 60: 1056-1060), and glycophorin C (Patel, S. S., et al., 2001. Blood 98:3489-3491), as well as variants in the TNF-α cytokine (McGuire, W. et al., 1994. Nature 371:508-510) and the CD36 scavenger receptor (Aitman, T. J. et al., 2000. Nature 405: 1015-1016) are also associated with protection against malaria. Additional linkage studies in Burkina Faso have suggested a complex genetic component of susceptibility showing blood parasitemia levels linked to the 5q31-q33 region (Rihet, P. et al., 1998. Am. J. Hum. Genet. 63: 498-505). The genetic component of malaria susceptibility is further modified by environmental factors (Kwiatkowski, D. 2000. Curr. Opin. Genet. Dev. 10: 320-324).
No efficacious vaccines are currently available to prevent or control the spread of parasitic diseases such as malaria, and most existing therapeutics are either not completely effective or toxic to the human host. Also, drugs often fail as a result of the selection and spread of drug resistant variants of the parasites. Notably, control of malaria has been hampered by the spread of drug resistance in both the Plasmodium parasites and the Anopheles insect vector, and by the lack of an efficacious vaccine (Moorthy, V. S. et al., 2004. Lancet 363: 150-156).
Therefore, there is a need to develop new approaches for the prevention and/or treatment of parasitic diseases such as malaria.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.